The immediate objective of this application is to develop and refine histotripsy (a novel, non-invasive ultrasound therapy that produces non-thermal mechanical tissue destruction) as a therapy for benign prostatic hyperplasia (BPH). The mechanism of tissue destruction is mediated by cavitation, a phenomenon where rapid cycling from compression to rarefaction results in formation of microbubbles within the tissue. The subsequent oscillation and violent collapse of these microbubbles mechanically breaks apart cellular and subcellular structures leaving a nonviable slurry of debris. This application seeks to foster the development of the investigator as a physician scientist by building upon established collaborations with Charles Cain, Ph.D. (Biomedical Engineering) and Brian Fowlkes, Ph.D. (Radiology and Biomedical Engineering). The career development plan combines didactic training in acoustical physics, guidance in experimental methods, and thoughtful mentorship from a cohesive, experienced researcher team. Initial tissue and acute in-vivo canine experiments are outlined to assess the susceptibility of different tissue types and anatomic structures to histotripsy induced bio-effects. This will provide insight into development of precise treatment strategies for prostate tissue fractionation and debulking without collateral damage. Using an in-vivo chronic canine model, studies are described to define the local and systemic response following histotripsy ablation of prostate tissue. PUBLIC HEALTH RELEVANCE: Prostate enlargement is a common finding in men as they age and causes difficulty with urination. Established treatments to remove this excess tissue and improve urinary drainage require invasive surgery. Less invasive alternatives that use heat to kill the excess prostate tissue have been developed but are not as effective, probably because the destroyed tissue is not actually removed. We propose to develop and test a novel technology called histotripsy, which uses ultrasound energy to mechanically break apart prostate tissue and converts it into a liquid that can be passed with urination. We believe this will result in widening of the urinary channel and improved urinary function without requiring invasive surgery.